Developing Nanopieces, a Platform RNAi Delivery Technology for Treatment of Multiple Diseases

开发 Nanopieces，一种用于治疗多种疾病的 RNAi 传递技术平台

基本信息

批准号：
9777769
负责人：
QIAN CHEN
金额：
$ 32.5万
依托单位：
NANODE THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-21 至 2023-02-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9777769
关键词：
ADAMTS Affect Affinity Amines Animal Model Base Pairing Biomimetics Cartilage Cartilage Matrix Cells Charge Chondrocytes Chondrogenic Neoplasm Chondrosarcoma Clinical Data DNA Data Degenerative polyarthritis Development Dimensions Disease Drug Delivery Systems Encapsulated Endocytosis Extracellular Matrix FDA approved Gene Expression Generations Genes Goals Half-Life Health Histology Hospitals Human In Vitro Joints Laboratories Liver Lysine Mission Nanotubes Nucleic Acids Outcome Penetration Peptide Hydrolases Pharmaceutical Preparations Phase Process Public Health RNA Interference RNA Interference Therapy RNA delivery Research Rheumatoid Arthritis Rhode Island Small Business Technology Transfer Research Small Interfering RNA Solid Neoplasm Surface Technology Testing Therapeutic Therapeutic Effect Time Tissues Toxic effect Transfection Translating United States National Institutes of Health Universities base biomaterial compatibility commercial application density disability in vivo innovation knock-down nanomaterials novel novel therapeutic intervention nucleic acid delivery pre-clinical response siRNA delivery small molecule therapeutic siRNA therapy outcome

项目摘要

STTR_Developing Nanopieces 7. Project Summary/Abstract The bottleneck of developing new RNAi (RNA Interference) drugs is the lack of highly efficient and non-toxic RNA delivery to non-liver tissues in vivo. It is especially challenging to deliver negatively-charged nucleic acid into avascular, dense, and negatively-charged matrix in hard-to-reach tissues including joint cartilage. NanoDe Therapeutics, Inc. (NanoDe) is a development stage company dedicated to developing delivery of RNAi therapeutics, thereby creating more effective drugs. NanoDe is founded on a novel platform RNA delivery technology termed NanopiecesTM, a novel biomimetic nanomaterial derived from a small molecule JBAK, Janus-Base with Amine or lysine (K). Through self-interaction of its biocompatible Janus-Base units mimicking DNA base pairs, JBAK forms non-covalent nanotubes (NT) with positively charged amine or lysine on the surface. JBAK NT further assembles with siRNA to form JBAK NP, thereby encapsulating negatively charged siRNA into positively charged NP. Our preliminary data has shown that 1) NPs can penetrate matrix-rich tissues that conventional vehicles cannot, and release siRNA therapeutics intracelluarly in high efficiency to modify otherwise untreatable diseases; 2) NP delivered RNAi therapeutics has achieved successful outcomes in the treatment of multiple diseases including rheumatoid arthritis, a rare solid tumor called chondrosarcoma, and post-traumatic osteoarthritis (PTOA) in animal models respectively; and 3) NP has excellent biocompatibility and biodegradability, which are critical for maintaining minimal toxicity in vivo. The goal of this Phase I application is to further develop NP delivery technology by using PTOA as a “use case” disease. The central hypothesis is that the optimal positive charge of NP is one of the critical parameters to enable its penetration into negatively charged cartilage matrix, endocytosis into chondrocytes, and release siRNA to inhibit disease gene expression, thereby achieving significant therapeutic effects on PTOA. This hypothesis will be tested with the two aims: 1) Determining the optimal charge of NP to enable its penetration and retention within cartilage tissue, transfection into chondrocytes, and inhibiting matrix proteinase ADAMTS-5 gene expression in chondrocytes, respectively; and 2) Determining the optimal charge of NP to enable its intra- articular delivery and long half-life within joint, and achieve significant therapeutic outcomes in a PTOA animal model. The proposed research is innovative because: 1) Essentially different from conventional delivery vehicles, Nanopiece is a non-covalent vehicle presenting unique advantages, such as versatility in dimensions and surface charge, affinity to extracellular matrix, excellent biodegradability and biocompatibility. 2) For the first time, we identify important technology parameters of NP required for successful siRNA delivery including the optimal vehicle surface charge for matrix penetration, cell transfection, and gene knockdown. 3) The technology breakthrough enlightens a therapeutic approach to deliver RNAi for treatment of multiple diseases including PTOA.

STTR_开发纳米片 7. 项目总结/摘要开发新型RNAi（RNA干扰）药物的瓶颈是缺乏高效、无毒的药物将 RNA 递送至体内非肝脏组织尤其具有挑战性。进入难以到达的组织（包括 NanoDe）中的无血管、致密和带负电的基质中。 Therapeutics, Inc. (NanoDe) 是一家处于开发阶段的公司，致力于开发 RNAi 的交付 NanoDe 建立在一个新的 RNA 递送平台上。名为 NanopiecesTM 的技术，一种源自小分子 JBAK 的新型仿生纳米材料， Janus-Base 与胺或赖氨酸 (K) 通过模仿其生物相容性 Janus-Base 单元的自相互作用。 DNA碱基对，JBAK与带正电荷的胺或赖氨酸形成非共价纳米管（NT） JBAK NT进一步与siRNA组装形成JBAK NP，从而封装带负电的。 siRNA 进入带正电荷的 NP。我们的初步数据表明 1) NP 可以穿透富含基质的物质。传统载体无法到达的组织，并在细胞内高效释放 siRNA 治疗剂改变其他无法治疗的疾病；2) NP 递送的 RNAi 疗法取得了成功的结果治疗多种疾病，包括类风湿性关节炎，一种称为软骨肉瘤的罕见实体瘤，和创伤后骨关节炎 (PTOA) 分别在动物模型中表现良好；3) NP 具有优异的疗效；生物相容性和生物降解性，这对于维持体内最小毒性至关重要。 I 期申请是通过使用 PTOA 作为“用例”疾病来进一步开发 NP 递送技术。中心假设是 NP 的最佳正电荷是使其能够实现的关键参数之一渗透到带负电荷的软骨基质中，内吞到软骨细胞中，并释放 siRNA 抑制疾病基因表达，从而实现对PTOA的显着治疗效果。测试有两个目的：1) 确定 NP 的最佳电荷以使其渗透和保留软骨组织内，转染软骨细胞，抑制基质蛋白酶ADAMTS-5基因分别在软骨细胞中表达；和 2) 确定 NP 的最佳电荷，以使其内部关节内递送和关节内半衰期长，并在 PTOA 动物中取得显着的治疗效果所提出的研究具有创新性，因为：1）与传统交付本质上不同。 Nanopiece 是一种非共价载体，具有独特的优势，例如尺寸的多功能性和表面电荷，对细胞外基质的亲和力，优异的生物降解性和生物相容性 2) 对于我们首次确定了成功 siRNA 递送所需的 NP 的重要技术参数，包括用于基质渗透、细胞转染和基因敲除的最佳载体表面电荷 3)。技术突破启发了一种治疗多种疾病的 RNAi 治疗方法包括PTOA。